neuroblastoma

Digital cases

 Case 223: Post-chemotherapy neuroblastic tumor

Definition: Poorly differentiated type of neuroblastic tumors.

Localization

 soft tissue

• retroperitoneal region, paravertebral region
• mediastinum
• pelvic region (#10813335#)
• urachus (#10382205#)

 urinary bladder (#12891516#, #11070482#, #10224211#)

Variants

 undifferentiated neuroblastoma
 poorly differentiated
 differentiating
 large cell neuroblastoma (#14716776#)
 ganglioneuroblastoma
 in situ neuroblastoma (#16010489#)

Age

 neonatal neuroblastoma (fetal neuroblastoma)
 infantile neuroblastoma
 adult neuroblastoma

Cytognetics

 constitutional translocation t(1;17)(p36;q12-21)
Ploidy

 hyperdiploidy (or near triploidy)

• lower stages
• favorable outcome

 Diploidy is a strong prognostic predictor of outcome.

Molecular biology

 gene amplifications

• MYCN gene amplification (MYCN-amplified neuroblastomas)
  • amplification of N-myc (MYCN) in neuroblastoma is strongly correlated with loss of 1p36 and gain of 17q.
  • more common in patients older than 1 year with advanced stages of the disease

 gene mutations

• NME1 (NM23) somatic mutations in advanced neuroblastoma (MIM.15490)

 gain of chromosome 17q

• unbalanced chromosome 17 translocations (#14695994#)
• not associated with poor prognosis (#14581355#)

 LOH - Allelotype: #11912152#, #15892104#

• 1p36 LOH
• 11q23 LOH (#10490829#)

CGH (#16075461#, #17823929#)

CGH Gains

1q gain
2p24 gain	MYCN
12q gain
17q23 gain

CGH Losses

1p32.1 loss
1p36.3 loss	25%-52%
3p21.31-3p22.1 loss
4p loss
5q35.2-5q35.3 loss
7q31.2 loss	31%
7q34 loss	31%
8qcen-q24 loss	26%
9q21-9q24.1 loss	26%
10p11-p15 loss	40%
10q26.11-10q26.12 loss
11q23-25 loss	42%
12q24.1 loss	26%
14q32 loss	37%
16q23.1-16q24.3 loss
18q21.32-18q23 loss
19q loss	31%		20p11.21-20p11.23 loss

Genetic subsets (#1325279#)

 1. hyperdiploid karyotype (or near-triploid karyotype)
 2. near-diploid karyotype with no consistent anomalies
 3. 1p36 LOH or MYCN amplification (or both) with near-diploid or tetraploid karyotype

 A subset of tumors with a clinically benign phenotype showed predominantly whole chromosome gains and losses. (#17647283#)

 Tumors with MYCN amplification had a unique genomic signature of 1p deletion and 17q gain, but few other rearrangements. (#17647283#)

 Tumors with an aggressive clinical phenotype without MYCN amplification, showed multiple structural rearrangements. Most notable were deletions of 3p, 4p, and 11q and gain of 1q, 2p, 12q, and 17q. (#17647283#)

 There is a subset of tumors with an aggressive clinical phenotype and no detectable DNA CNAs. (#17647283#)

Miscellaneous

 schwannian cells and neuroblastic cells have the same genetic alterations ? (#11107110#, #11559566#)
 CpG-island hypermethylation of gene promoters: #14506696#

Predisposition

 abnormal constitutional karyotypes in patients with neuroblastoma

• mosaicism for monosomy 22
• constitutional 11q interstitial deletion (#14662434#, #14623457#)
• pericentric inversion of chromosome 9 at band 9p21
• robertsonian translocation t(13;14)
• 47, XXX karyotype (#14499703#)

 familial neuroblastoma (#12880958#)

• germline mutations of the paired-like homeobox 2B PHOX2B gene (#15024693#)

 probable excess of neuroblastoma in patients with Turner syndrome (#14623457#)

Constitutional chromosomal anomalies

 mosaicism for monosomy 22
 11q interstitial deletion
 pericentric inversion of chromosome 9 at band 9p21
 Robertsonian translocation t(13;14)

 chromosomal rearrangements

• 1p36
• 2p23
• 3q
• 11q23
• 15q
• 1p
• 2p
• 9p
• 11q
• 16q
• 17q

Hypermethylation

 Frequent promoter hypermethylation of RASSF1A and CASP8 in neuroblastoma (#17064406#)

See also

 neuroblastic tumors

• neuroblastoma
• ganglioneuroblastoma
• ganglioneuroma

Pathology reviews

 Joshi VV. Peripheral neuroblastic tumors: pathologic classification based on recommendations of international neuroblastoma pathology committee (Modification of shimada classification). Pediatr Dev Pathol. 2000 Mar-Apr;3(2):184-99. PMID: #10679039#

References - CGH and genetics

 Predicting outcomes for children with neuroblastoma using a multigene-expression signature: a retrospective SIOPEN/COG/GPOH study. Vermeulen J, De Preter K, Naranjo A, Vercruysse L, Van Roy N, Hellemans J, Swerts K, Bravo S, Scaruffi P, Tonini GP, De Bernardi B, Noguera R, Piqueras M, Cañete A, Castel V, Janoueix-Lerosey I, Delattre O, Schleiermacher G, Michon J, Combaret V, Fischer M, Oberthuer A, Ambros PF, Beiske K, Bénard J, Marques B, Rubie H, Kohler J, Pötschger U, Ladenstein R, Hogarty MD, McGrady P, London WB, Laureys G, Speleman F, Vandesompele J. Lancet Oncol. 2009 Jul;10(7):663-71. Epub 2009 Jun 8. PMID: #19515614#

 Overall genomic pattern is a predictor of outcome in neuroblastoma. Janoueix-Lerosey I, Schleiermacher G, Michels E, Mosseri V, Ribeiro A, Lequin D, Vermeulen J, Couturier J, Peuchmaur M, Valent A, Plantaz D, Rubie H, Valteau-Couanet D, Thomas C, Combaret V, Rousseau R, Eggert A, Michon J, Speleman F, Delattre O. J Clin Oncol. 2009 Mar 1;27(7):1026-33. PMID: #19171713#

 Microtubule-associated protein-2 is a sensitive marker of primary and metastatic neuroblastoma. Krishnan C, Higgins JP, West RB, Natkunam Y, Heerema-McKenney A, Arber DA. Am J Surg Pathol. 2009 Nov;33(11):1695-704. PMID: #19701075#

 ArrayCGH-based classification of neuroblastoma into genomic subgroups. Michels E, Vandesompele J, De Preter K, Hoebeeck J, Vermeulen J, Schramm A, Molenaar JJ, Menten B, Marques B, Stallings RL, Combaret V, Devalck C, De Paepe A, Versteeg R, Eggert A, Laureys G, Van Roy N, Speleman F. Genes Chromosomes Cancer. 2007 Sep 6; PMID: #17823929#

 Neuroblastomas have distinct genomic DNA profiles that predict clinical phenotype and regional gene expression. Mosse YP, Diskin SJ, Wasserman N, Rinaldi K, Attiyeh EF, Cole K, Jagannathan J, Bhambhani K, Winter C, Maris JM. Genes Chromosomes Cancer. 2007 Oct;46(10):936-49.
PMID: #17647283#

 Genome-Wide Analysis of Neuroblastomas using High-Density Single Nucleotide Polymorphism Arrays. George RE, Attiyeh EF, Li S, Moreau LA, Neuberg D, Li C, Fox EA, Meyerson M, Diller L, Fortina P, Look AT, Maris JM. PLoS ONE. 2007 Feb 28;2:e255. PMID: #17327916#

 High-resolution analysis of allelic imbalance in neuroblastoma cell lines by single nucleotide polymorphism arrays. Carr J, Bown NP, Case MC, Hall AG, Lunec J, Tweddle DA. Cancer Genet Cytogenet. 2007 Jan 15;172(2):127-38. PMID: #17213021#

 Oligonucleotide array-based comparative genomic hybridization (aCGH) of 90 neuroblastomas reveals aberration patterns closely associated with relapse pattern and outcome. Spitz R, Oberthuer A, Zapatka M, Brors B, Hero B, Ernestus K, Oestreich J, Fischer M, Simon T, Berthold F. Genes Chromosomes Cancer. 2006 Dec;45(12):1130-42. PMID: #16958102#

 Integrative genomics identifies distinct molecular classes of neuroblastoma and shows that multiple genes are targeted by regional alterations in DNA copy number. Wang Q, Diskin S, Rappaport E, Attiyeh E, Mosse Y, Shue D, Seiser E, Jagannathan J, Shusterman S, Bansal M, Khazi D, Winter C, Okawa E, Grant G, Cnaan A, Zhao H, Cheung NK, Gerald W, London W, Matthay KK, Brodeur GM, Maris JM. Cancer Res. 2006 Jun 15;66(12):6050-62. PMID: #16778177#

 Maris JM, Hii G, Gelfand CA, Varde S, White PS, Rappaport E, Surrey S, Fortina P. Region-specific detection of neuroblastoma loss of heterozygosity at multiple loci simultaneously using a SNP-based tag-array platform. Genome Res. 2005 Aug;15(8):1168-76. PMID: #16077016#

 Chen QR, Bilke S, Khan J. High-resolution cDNA microarray-based comparative genomic hybridization analysis in neuroblastoma. Cancer Lett. 2005 Oct 18;228(1-2):71-81. PMID: #15951107#

 Maris JM. The biologic basis for neuroblastoma heterogeneity and risk stratification. Curr Opin Pediatr. 2005 Feb;17(1):7-13. PMID: #15659956#

 Pahlman S, Stockhausen MT, Fredlund E, Axelson H. Notch signaling in neuroblastoma. Semin Cancer Biol. 2004 Oct;14(5):365-73. PMID: #15288262#

 Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 2003 Mar;3(3):203-16. PMID: #12612655#

 Vandesompele J, Speleman F, Van Roy N, Laureys G, Brinskchmidt C, Christiansen H, Lampert F, Lastowska M, Bown N, Pearson A, Nicholson JC, Ross F, Combaret V, Delattre O, Feuerstein BG, Plantaz D. Multicentre analysis of patterns of DNA gains and losses in 204 neuroblastoma tumors: how many genetic subgroups are there? Med Pediatr Oncol. 2001 Jan;36(1):5-10. PMID: #11464905#

 Maris JM, Matthay KK. Molecular biology of neuroblastoma. J Clin Oncol. 1999 Jul;17(7):2264-79. PMID: #10561284#

 Mora J, Cheung NK, Kushner BH, LaQuaglia MP, Kramer K, Fazzari M, Heller G, Chen L, Gerald WL. Clinical categories of neuroblastoma are associated with different patterns of loss of heterozygosity on chromosome arm 1p. J Mol Diagn. 2000 Feb;2(1):37-46. PMID: #11272900#

 Brodeur GM, Azar C, Brother M, Hiemstra J, Kaufman B, Marshall H, Moley J, Nakagawara A, Saylors R, Scavarda N, et al. Neuroblastoma. Effect of genetic factors on prognosis and treatment. Cancer. 1992 Sep 15;70(6 Suppl):1685-94. PMID: #1325279#